This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The primary objective is to identify factors that contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). Development of disease biomarkers and diagnostic laboratory tests would facilitate earlier treatment intervention, help monitor treatment efficacy;and, ultimately, lead to the identification of targets that could be used in therapy development. Specific aim 1 is to develop a laboratory test that can be used by primary care physicians, neurologists and other clinicians to provide guidance with regard to something to worry about (possible ALS). It would provide benefit in generating appropriate referrals to neurological specialists early in disease progression. False negatives could be tolerated but false positives cannot (i.e. high specificity required with acceptable sensitivity). The test will identify people with ALS and distinguish ALS from disorders that present with similar symptoms (e.g. carpal tunnel, radiculopathies, myopathies). A test with high sensitivity for ALS can be very useful for specialty neurologist as well for early and accurate detection for inclusion in clinical trials. Blood and CSF samples will be collected at multiple sites representing the four regions of the United States from age and gender matched healthy individuals, disease mimics, and ALS patients. Specific aim 2 is to assess how biomarkers discovered in aim 1 change with disease course. Blood samples will be collected longitudinally from ALS and suspected ALS volunteers.